GeneBe

rs1060504694

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007194.4(CHEK2):​c.847-11_847-10delCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,391,792 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

Publications

0 publications found
Variant links:
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
CHEK2 Gene-Disease associations (from GenCC):
  • CHEK2-related cancer predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
  • Li-Fraumeni syndrome 2
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • acute myeloid leukemia
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHEK2NM_007194.4 linkc.847-11_847-10delCC intron_variant Intron 7 of 14 ENST00000404276.6 NP_009125.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHEK2ENST00000404276.6 linkc.847-11_847-10delCC intron_variant Intron 7 of 14 1 NM_007194.4 ENSP00000385747.1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
7.18e-7
AC:
1
AN:
1391792
Hom.:
0
AF XY:
0.00000144
AC XY:
1
AN XY:
693572
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32116
American (AMR)
AF:
0.00
AC:
0
AN:
41434
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25356
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39206
South Asian (SAS)
AF:
0.0000121
AC:
1
AN:
82680
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52204
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5678
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1055116
Other (OTH)
AF:
0.00
AC:
0
AN:
58002
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1060504694; hg19: chr22-29099563; API